The X-linked immunodeficiency of CBA/N mice is caused by a gene on the X- chromosome designated xid. This defect is characterized by unresponsiveness to polysaccharide antigen, low serum IgM and IgG3 levels and diminished numbers of B cells. In order to positionally clone this gene, an F1 between CBA/N and Mus musculus Skive mice was made. The F1 females were crossed to male CBA/N mice. A backcross of over 1100 animals was typed for xid phenotype and for a variety of genetic markers. This led to the precise mapping of xid on the mouse X-chromosome. Indeed, a simple sequence repeat marker, DXMit3, failed to recombine with xid in any of the members of the backcross. A set of YACs was obtained that expressed DXMit 3. The fine mapping of xid indicated that it was in a region of the mouse X chromosome homologous to the region in which the gene determining human X-linked agammaglobulinemia (Xla) was found. This disease is cause by mutations in the kinase domain of the Bruton~s agammaglobulinemia tyrosine kinase (btk). Using btk specific primers, it was shown that DXMit 3 positive YACs all bore btk. Moreover, based on a polymorphism in btk, it was shown that no recombinations existed between btk and xid. Sequencing of btk of CBA/N mice and of their nearest relative, CBA/CaHN, revealed a point mutation that converted position 28, within the unique domain of the kinase, from arginine to cysteine. In a total of 7 mammalian species, position 28 of btk is always arginine, arguing that this point mutation is very likely the cause of the xid-determined immune defect. Studies of Ig class switching have been carried out with a quantitative and specific assay, digestion-circularization PCR (DC-PCR), which allows one to measure the progress of DNA deletion in the course of the switching process. In B cells stimulated with lipopolysacchartide (LPS) and IL-4, a high degree of switching to IgG1 occurs. DC-PCR assay reveals that there is sufficient DNA deletion occurring in the course of in vitro switching to account for all switched cells. This indicates that, if other mechanisms play a role in switching, they do so mainly as a prelude to deletional switching.